It is estimated that almost 30% of people in the US endure chronic pain. While certain drugs can control some types of pain, many have limitations as well as dose-limiting side effects. Thus safer, more specific drugs would have high clinical utility. Recent studies have shown that the metabotropic glutamate receptor, mGluR5, plays a role in the development and maintenance of chronic pain such that pharmacological antagonism of mGluR5 is thought to be analgesic. Intriguingly, mGluR5, not only plays a critical role on the plasma membrane but also an unknown but profound role on nuclear membranes of the spinal cord neurons that are associated with chronic inflammatory pain. For example, increased levels of mGluR5 are found on nuclear membranes of spinal cord dorsal horn neurons in rats with neuropathic pain. To date the specific role of intracellular mGluR5 has been completely overlooked in any neuronal type including dorsal horn neurons, despite studies showing 60-90% of the receptor is on intracellular membranes. Thus a clearer understanding of the specific role played by spinal intracellular mGluR5 in chronic inflammatory pain could provide a strong rationale for the development of restricted antagonists as novel pain therapeutics. It is therefore the goal of this proposal to examine the role of spinal intracellular mGluR5 in chronic inflammatory pain. Specifically we hypothesize that intracellular mGluR5 plays an important role in modulating chronic pain models. Using pharmacological, biochemical, and molecular techniques, we address the following questions: Does blockade of cell surface mGluR5 with an impermeable antagonist (LY393053) prevent downstream sequelae of glutamate induced inflammation or neuropathic injury; and 2) what are the underlying signaling mechanisms associated with intracellular mGluR5-dependent chronic inflammatory pain. These studies will reveal the cellular and molecular mechanisms by which mGluR5 modulates chronic pain, and will clearly define the role of intracellular receptors in an in vivo setting. Subsequent studies wll assess downstream targets altered by mGluR5 signaling. Inasmuch as mGluR5 is involved in both peripheral and central sensitization it represents an attractive target for drug discovery. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for chronic inflammatory pain.